U.S. Pat. No. 5,061,703 discloses a general method for the preparation of aminoalkyladamantanes. The synthesis comprises three steps: halogenation of alkyladamantanes with elemental chlorine or bromine; formylation of the halogenated alkyladamantanes with formamide. The final acid hydrolysis gives a range of aminoalkyladamantanes.
This method employs hazardous and toxic reagents (in particular chlorine or bromine) and the synthesis typically requires a large excess of the key reagents. This generates a considerable amount of waste, which is not desirable, among others, from an environmental and an economic point of view.
Another method for the direct preparation of N-Formyl-1-amino-3,5-dimethyladamantane from 1,3-dimethyladamantane (1,3-DMA) using strong acids and formamide was described by L. Wanka, C. Cabrele, M. Vanejews, and P. R. Schreiner in Eur. J. Org. Chem. 2007, 1474-1490.
A similar process is disclosed in WO 2007/101536 A1. However, the process described in these publications still has several drawbacks. Although the process avoids the use of elemental bromine, the overall process still results in considerable waste as it employs a large excess of formamide (63 molar equivalents), sulphuric acid (22 molar equivalents, 8 volume parts per weight part of 1,3-DMA), and nitric acid (1.8 molar equivalents), all of which need to be disposed and/or carried through the working-up procedure. Besides, a large amount of halogenated organic solvents must be used in said process in order to extract the product from the mixture. Furthermore an additional purification step by chromatography is reported, which may not be economically viable on the industrial scale.